A novel guaiane sesquiterpene derivative, guai-2-en-10α-ol, from Ulva fasciata Delile inhibits EGFR/PI3K/Akt signaling and induces cytotoxicity in triple-negative breast cancer cells

Abstract

A novel guaiane sesquiterpene derivative, guai-2-en-10α-ol, from Ulva fasciata Delile exhibits antimicrobial property. U. fasciata extract was reported to exhibit cytotoxicity against cancer. In the present study, we have studied the anticancer potential of the compound, guai-2-en-10α-ol, from U. fasciata. The compound showed selective cytotoxicity toward triple-negative breast cancer (TNBC) cell line (MDA MB-231) in a dose-dependent manner. In treated cells, the apoptotic hallmarks such as formation of apoptotic bodies, cell shrinkage, and nuclear condensation were observed. Many small molecules affect the function of cellular signaling pathways. As EGFR/PI3K/Akt pathway proteins are frequently altered in TNBC, we have studied the gene expression of key proteins of this pathway. The semiquantitative PCR results demonstrated the down-regulated expression of PDPK1 (positive regulator) and Akt (key activator) as well as up-regulated expression of PTEN (negative regulator), which suggested the interaction of guai-2-en-10α-ol with upstream protein. Further investigation showed the down-regulation of both PI3K and EGFR. As EGFR is the most upstream protein of the pathway, its protein level expression was investigated. Western blotting analysis confirmed the down-regulation of p-EGFR expression and activation of apoptosis upon compound treatment. Cell cycle analysis also evidenced the G1 phase arrest, which can be due to the inhibition of cell survival pathway. Computational studies showed the interaction of guai-2-en-10α-ol with Asp855 residue of EGFR kinase domain in active conformation. All these results demonstrate the anticancer potential of guai-2-en-10α-ol through EGFR/PI3K/Akt pathway.

Anticancer Activities of Meroterpenoids Isolated from the Brown Alga Cystoseira usneoides against the Human Colon Cancer Cells HT-29

“…These results are in line with an earlier report that demonstrated that the algal halogenated monoterpene mertensene induced similar response with G2/M arrest from HT-29 cells [33]. However, other algal terpenes have been described to induce cell cycle arrest in G1 phase in different types of cell lines [36,37]. Cancer metastasis is a leading cause of death in cancer patients.…”

“…In particular, the AMT tuberatolide B, isolated from the alga Sargassum macrocarpum [31], has been shown to inhibit the viability of various cancer cell lines, including breast cancer (MDA-MB-231), lung cancer (A549), and colon cancer (HCT116), by inducing apoptotic cell death, and sargachromanol E, from Sargassum siliquastrum, has been reported to induce apoptosis in the colon cancer cell line HL-60 [32]. On the other hand, in the last years a variety of algal terpenoids have been reported to induce apoptosis in several cancer cells, including HT-29 [33], Jurkat leukemic cells [34], melanoma B16F10 cells [35,36], and human TNBC cells [37].…”

“…Nonetheless, some studies on the mechanism of action of other algal terpenoids have also demonstrated the intervention of other signaling pathways. For example, the sesquiterpene guai-2-en-10α-ol, from Ulva fasciata, was reported to induce apoptosis and cell cycle arrest in G1 phase of triple-negative breast cancer (TNBC) cell line (MDA MB-231) via regulation of EGFR/PI3 K/Akt pathway [37] and laurinterol, from Laurencia okamurae, showed anticancer activity against melanoma cells (B16F1) through the p53-dependent pathway [65].…”

Bioactive Metabolites from Marine Algae as Potent Pharmacophores against Oxidative Stress-Associated Human Diseases: A Comprehensive Review

“…Moreover, fucoxanthinol displayed an anti-proliferative effect against drug-resistant HT-29-derived cells, and inhibited xenograft tumor development in a dose-dependent manner [81]. The guaiane sesquiterpene derivative guai-2-en-10-ol isolated from the green seaweed Ulva fasciata, reduced viability of breast cancer MDA-MB-231 cell line [82]. G. tenuistipitata aqueous extract counteracted the cellular proliferation in H1299 cells.…”

“…Dieckol from E. cava daily administration (40 mg/kg for 15 weeks) decreased cancer cell proliferation in albino rats via induction of apoptosis [95]. The guaiane sesquiterpene derivative guai-2-en-10-ol from green seaweed Ulva fasciata induced apoptosis in MDA-MB-231 breast cancer cell line via direct interaction with the kinase site of EGFR [82]. The halogenated monoterpene, mertensene from red alga Pterocladiella capillacea induced apoptosis in HT-29 and LS174 via modulation of ERK1/2, Akt, and NF B pathways [78].…”